Scientists Modify Viruses With CRISPR To Create New Weapon Against Superbugs

About two years ago, Alphonso Evans went to the hospital for what he thought was just another bladder infection and ended up in intensive care. In an effort to combat antibiotic-resistant superbugs, scientists have created "living antibiotics" made of viruses that have been genetically modified using the gene-editing tool CRISPR.

Rob Stein/NPR

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Originally published on May 22, 2019 8:49 pm

Alphonso Evans rolls his wheelchair into a weight machine in the gym at the Charlie Norwood VA Medical Center in Augusta, Ga.

"I'm not so much worried about dying from a heart attack or diabetes, because I'm active. I know what to do to work against it: watch what I eat, exercise," Evans says. "But what do I do about an infection? Or fighting off a bacteria — something inside me that I don't see until it's too late?"

Evans, 67, is fully paralyzed from the chest down and has only partial use of his hands. And like a lot of spinal cord injury patients, he's prone to infections, especially bladder infections.

About two years ago, he came to the VA medical center for what he thought was just another bladder infection. Turns out, he also had a bone infection and developed pneumonia. He ended up in intensive care. "It scared me," says Evans, who lives nearby in Hephzibah, Ga. "And I don't scare easy."

Bladder infections, like many others, are increasingly becoming resistant to antibiotics.

"We are getting to the point where there are organisms that are resistant to every known antibiotic," says Michael Priebe, a doctor who heads the spinal cord injury service at the VA medical center.

"My fear is that as we are in this arms race, there gets to the point where we are not able to keep up with the enemy — the resistant bacteria. The superbugs take over, and we have nothing to defend against it," Priebe says.

So Priebe enlisted Evans to help develop a different way to fight superbugs. It's a new kind of antibiotic made out of viruses that have been genetically modified using the gene-editing tool CRISPR.

"What CRISPR is able to do is something that we've not been able to do before. And that is, very selectively modify genes in the viruses to target the bacteria," Priebe says.

Later this year, Dr. Michael Priebe and his colleagues plan to start infusing cocktails containing billions of bacteriophages genetically modified with CRISPR into patients at six centers around the United States.

Rob Stein/NPR

"If we're successful, this revolutionizes the treatment of infections," he adds. "This can be the game changer that takes us out of this arms race with the resistant bacteria and allows us to use a totally different mechanism to fight the pathogenic bacteria that are infecting us."

The approach, developed by Locus Biosciences of Morrisville, N.C., involves viruses known as bacteriophages (called phages for short). Phages are the natural enemies of bacteria. They can infect and destroy bacteria by reproducing in large numbers inside them until the microbes literally explode.

Locus scientists have created a cocktail of three phages that have been modified using CRISPR, which was discovered by studying the immune systems of bacteria.

"What we've learned how to do is reprogram that immune system to attack itself," says Paul Garofolo, the company's CEO. "We load the viruses up with CRISPR constructs, which essentially work like little Pac-Men. They go into a target bacteria cell, and they chew up the DNA of that target. It makes them much more potent killers."

Locus is one of several companies that are trying to use CRISPR to fight health problems by targeting only bad bacteria in the body and leaving the good ones alone.

"I think it's really exciting," says Steffanie Strathdee, who studies phages at the University of California San Diego. "We've been using antibiotics, which really have a scorched-earth approach to the treatment of infections. They don't just kill the bacteria that we want to kill. They kill friendly bacteria in our microbiome as well."

The microbiome comprises the trillions of friendly microbes that inhabit the human body.

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"The potential is to groom the microbiome — to weed out unhealthy bacteria and to promote the growth of healthy bacteria in our microbiome," says Strathdee, who wrote the book The Perfect Predator, about a last-ditch bacteriophage treatment to save her husband.

Other scientists agree that the strategy is promising, especially given the threat posed by superbugs.

"I think it's an intriguing approach. It's kind of a really smart approach," says Graham Hatfull, a professor of biological sciences at the University of Pittsburgh who specializes in phage research. He was part of a team that recently used genetically modified phages to try to treat a superbug infection for the first time.

But Hatfull worries that not enough research has been done so far to really understand bacteriophages.

"In some senses, using engineered phages is going to be a bit like running before you can walk. It's hard to improve something without knowing about how the thing you're trying to improve works," Hatfull says.

And there's always the chance it could backfire.

"The concern is that you could essentially end up converting harmless bacteria into potentially dangerous ones," Hatfull says.

Priebe acknowledges there could be dangers and says that's why the first tests are aimed primarily at making sure the CRISPR-modified phages are safe.

"We have to take things slowly," Priebe says. "We don't know how things are going to evolve."

Later this year, he and his colleagues plan to start infusing cocktails containing billions of phages genetically modified with CRISPR into patients like Evans twice a day for seven days at six centers around the United States.

The study will involve 30 patients. Twenty of them will get the engineered phage cocktail, and 10 will get a placebo. The researchers will then follow the volunteers and conduct extensive tests of their blood and urine to see if the approach is safe and affects the levels of E. coli bacteria in their urinary tracts. If that's the case, the company plans more research to see how well the approach might fight infections.

In preparation for the study, Priebe plans to study about 200 paralyzed patients, including Evans, to get a better sense of the natural course of E. coli colonization of the urinary tract in paralyzed patients.

Evans says he's also ready to volunteer for the treatment stage of Priebe's research.

"I think it's a great idea," he says.

Evans served in the military for 25 years, including a tour in Vietnam and stints in South Korea and Germany. But he wasn't paralyzed while fighting overseas.

"That's what's ironic," Evans says. "Twenty-five years in the Army and never got injured. Nothing. Two days before retirement, I was driving down the street. This kid was shooting at cars. And he shot me through the back."

Ever since, he has been struggling with medical problems, including repeated urinary tract infections.

"Just the fact that the research is going on gives us hope," Evans says.

Copyright 2020 NPR. To see more, visit https://www.npr.org.

STEVE INSKEEP, HOST:

Scientists think they have a way to fight infections when antibiotics fail. Doctors report increasing danger from drug-resistant infections, and they're hoping a gene editing technique offers a solution. The technique known as CRISPR may help to create super predators to go after superbugs. Here's NPR health correspondent Rob Stein.

ROB STEIN, BYLINE: Superbugs are bacteria that can beat modern medicine's most powerful weapons - antibiotics. So doctors are racing to find new ways to fight back, doctors like Michael Priebe at the VA Medical Center in Augusta, Ga.

MICHAEL PRIEBE: Morning, Mr. Evans.

ALPHONSO EVANS: How are you doing, Dr. Priebe?

PRIEBE: All right. How are you?

EVANS: Fine, fine.

STEIN: That's where I met Dr. Priebe and one of his patients, Alphonso Evans.

PRIEBE: You look good this morning.

EVANS: Thank you. I feel good, too.

STEIN: Evans is a retired Army master sergeant. He's paralyzed from the chest down, but not from his service overseas.

EVANS: That's what's ironic - 25 years in the Army and never got injured. I was in Vietnam, and I was in Korea. My first tour in Germany, Baader–Meinhof Gang was blowing up things around where I was stationed - nothing. Two days before retirement, I was driving down the street; this kid was shooting at cars, and he shot me through the back.

STEIN: That was in Wichita, Kan. Ever since, Evans - who's 67 - has been struggling with lots of medical problems. Two years ago, he went to the VA for what he thought was just another bladder infection and ended up in intensive care.

STEIN: Now, it's unclear exactly why Evans got so sick - turns out he had a bone infection, too, then got pneumonia - and he's doing well now. But urinary tract infections are a huge problem for paralyzed people like Evans, and Dr. Priebe says those infections are getting harder and harder to cure.

PRIEBE: We are getting to the point where there are organisms that are resistant to every known antibiotic. My fear is that as we are in this arms race, there gets to a point where we are not able to keep up with the enemy, the resistant bacteria. The superbugs take over, and we have nothing to defend against it.

STEIN: So Priebe is leading the first attempt to test an entirely new way to fight superbugs - a new kind of antibiotic, a living antibiotic, made out of live viruses that have been genetically modified using the gene editing tool CRISPR.

PRIEBE: If we're successful with this, this revolutionizes the treatment of infections in the world today. This can be the game-changer that takes us out of this arms race with the resistant bacteria and allows us to use a totally different mechanism to fight the pathogenic bacteria that are infecting us.

Good morning, sir.

RICKY MCNEIL: Good morning, sir.

PRIEBE: How are you today?

MCNEIL: I'm good. How are you doing?

STEIN: In another part of the hospital, I meet another paralyzed vet, Ricky McNeil (ph). He's also been plagued by antibiotic-resistant bladder infections. Dr. Priebe and one of his colleagues, Chris Myers, are explaining the studies they're launching to test this new kind of antibiotic.

CHRIS MYERS: The study sponsor is Locus Bioscience (ph), and this company is going to use what's called a - it's a bacterial phage, which is a type of virus that attacks specific types of bacteria.

MCNEIL: Yes, sir.

STEIN: Bacteriophages are the natural enemies of bacteria. The scientists are trying to turn them into superbug killers by using CRISPR to hijack the bacteria's own immune systems, which is where scientists discovered CRISPR in the first place, and turn that against the bacteria to literally shred their DNA.

PRIEBE: What CRISPR is able to do is something that we've not been able to do before, and that is very selectively modify genes to target the bacteria. This provides us with a new weapon that we can target against the enemy.

MCNEIL: OK.

STEIN: The company sponsoring the study is one of several trying to use CRISPR like this - to fight lots of health problems by targeting only bad bacteria in the body and leaving the good ones alone. Stephanie Straftey (ph) is at the University of California, San Diego.

STEPHANIE STRAFTEY: Well, I think it's really exciting because we've been using antibiotics, which really have a scorched-earth approach to the treatment of infections. So they don't just kill the bacteria that we want to kill; they kill friendly bacteria in our microbiome, as well.

STEIN: The microbiome is the trillions of friendly microbes that inhabit the human body.

STRAFTEY: The potential is to groom the microbiome to weed out unhealthy bacteria and to promote the growth of healthy bacteria in our microbiome.

STEIN: Other scientists agree the approach is promising, especially given the threat posed by superbugs. Graham Hatfull studies bacteriophages at the University of Pittsburgh.

GRAHAM HATFULL: So I think it's a really intriguing approach. It's kind of a smart approach.

STEIN: But Hatfull worries not enough research has been done first to really understand bacteriophages, known as phages for short.

HATFULL: In some sense, using engineered phages is going to be a bit like running before you can walk; it's hard to improve something without knowing about how the thing you're trying to improve works.

STEIN: There's always a chance it could backfire.

HATFULL: The concern is, is that you could essentially end up converting harmless bacteria into potentially dangerous ones.

STEIN: Dr. Priebe acknowledges there could be dangers; that's why the first tests are aimed primarily at making sure CRISPR-modified phages are safe.

PRIEBE: We have to take things slowly. We don't know how things are going to evolve.

STEIN: But one of the vets we met at the beginning of this story, Alphonso Evans, is ready to volunteer. I caught up with him again at the VA hospital gym, where he was lifting weights from his wheelchair.

EVANS: ...Eighteen, 19, 20.

I'm not so much worried about dying from a heart attack or diabetes because I'm active. I know what I need to do to work against it - you know, watch what I eat, exercise. But what do I do about an infection or fighting off a bacteria, something inside me that I don't see until it's too late? Just the fact that the research is going on gives us hope.

STEIN: Later this year, Priebe and his colleagues plan to start infusing billions of phage viruses that have been genetically modified with CRISPR into patients like Evans.